Consumer medicine information

Zeldox IM

Ziprasidone

BRAND INFORMATION

Brand name

Zeldox IM

Active ingredient

Ziprasidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zeldox IM.

What is in this leaflet

This leaflet answers some common questions about Zeldox IM.

It does not contain all the available information.

It does not take the place of talking to your doctor or nurse.

All medicines have risks and benefits. Your doctor has weighed the risks of treatment with Zeldox IM against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or nurse.

Keep this leaflet with the medicine. You may need to read it again.

What Zeldox IM is used for

What Zeldox IM is for

Zeldox IM is used to treat severe agitation or aggression in people with schizophrenia or similar illnesses.

Your doctor may have prescribed Zeldox IM for another reason.

Ask your doctor if you have any questions about why Zeldox IM has been prescribed for you.

After you have been given Zeldox IM, your symptoms should get better. Your doctor may then switch you to Zeldox capsules or another oral medicine to help manage your symptoms in the long term.

How Zeldox IM works

Zeldox IM belongs to a group of medicines called antipsychotics. It contains the ingredient ziprasidone.

Ziprasidone is thought to work by correcting the imbalance of some chemicals in the brain. This, in turn, reduces the agitation or aggression caused by the illness.

Using Zeldox IM

Zeldox IM is an injection. It is available only in a hospital with a doctor's prescription.

Only a doctor or nurse can give the injection.

Zeldox IM is not recommended for the treatment of elderly patients with dementia-related psychosis.

Zeldox IM is not recommended for use in children under 18 years of age. There is not enough information on its effects in this age group.

Before you are given Zeldox IM

When it must not be used

You must not be given Zeldox IM if you have an allergy to:

  • any medicine containing ziprasidone
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to Zeldox IM may include:

  • hives, itching or skin rash
  • shortness of breath, wheezing
  • swelling of the face, lips or tongue which may lead to difficulty swallowing or breathing.

You should not be given Zeldox IM if you have had any of the following medical conditions. Your doctor or nurse need to know if you have ever had:

  • a recent heart attack
  • heart failure that is not well-controlled
  • abnormal rhythm of the heart or any other condition requiring other drugs to control your heart rhythm.

Before you are given it

Your doctor and nurse need to know if you have any allergies to:

  • any other medicines
  • any other substances such as foods, preservatives or dyes.

Your doctor and nurse need to know about all your medical conditions, especially if you have ever had any of the following:

  • irregular heart rate
  • a condition requiring other drugs to control the heart rhythm
  • any heart or blood vessel problems
  • low blood levels of potassium or magnesium
  • high sugar levels in your blood
  • a condition that may give you low blood pressure
  • kidney problems
  • a history of seizures (fits)
  • liver problems
  • headache
  • nausea
  • vomiting
  • blurred vision
  • muscle weakness
  • if you are 65 years of age or over and have a condition known as dementia-related psychosis
  • if you have ever suffered or suffers from a condition called deep vein thrombosis (DVT). DVT is the formation of blood clots in one of the deep veins within the body, e.g., the leg or pelvis. The symptoms of DVT are pain and swelling in your legs. Sometimes the blood clot may break away from its original location and travel to the lungs. This condition is called pulmonary embolism (PE). Symptoms of PE may include sharp chest pain, shortness of breath or you may cough up blood
  • breathing stops and starts while sleeping.

Your doctor and nurse need to know if you have ever had any of the following reactions to this type of medicine:

  • Neuroleptic Malignant Syndrome (NMS) - symptoms include sudden fever, fast breathing, blood pressure changes, sweating, confusion, muscle stiffness and drowsiness or sleepiness
  • Tardive Dyskinesia (TD) - unusual movements (mainly of the face and tongue), or uncontrollable twitching or jerking of the arms and legs.

Your doctor and nurse need to know if:

  • you are pregnant
  • you are breastfeeding.

Like most antipsychotic medicines, Zeldox IM is not recommended for use during pregnancy or during breastfeeding. It is thought that low levels of Zeldox passes into breast milk.

Babies exposed to antipsychotic drugs (including Zeldox) during the third trimester of pregnancy are at risk of experiencing agitation, abnormal muscle tone, tremor, somnolence, breathing problems, difficulty in feeding and/or withdrawal symptoms after being born

Taking other medicines

Some medicines may be affected by Zeldox IM or may affect how well it works. Your doctor may need to give you different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

Your doctor and nurse need to know if you are taking any other medicines, including:

  • all prescription medicines
  • all medicine bought over-the-counter from a pharmacy or supermarket
  • all complementary and alternative therapies
  • any supplements or herbal remedies bought from a health food shop
  • a type of herbal medicine to treat depression called St John's Wort (Hypericum perforatum)
  • any illicit drugs.

Your doctor and nurse need to know if you are taking medicines for any of the following medical conditions:

  • Parkinson's disease
  • Schizophrenia or other psychoses
  • fast or irregular heart rhythms
  • sedatives to help you sleep
  • anxiety
  • depression or mood swings
  • pain - especially any narcotic
  • epilepsy or mood disorder - especially carbamazepine
  • fungal infections - especially ketoconazole
  • rifampicin an antibiotic used for the treatment of tuberculosis.

Your doctor or nurse has more information on medicines to be careful with or to avoid while using Zeldox IM.

How Zeldox IM is given

Your doctor will decide how much Zeldox IM you need.

A doctor or nurse will inject Zeldox IM into a muscle.

Your doctor may use Zeldox IM for up to three days.

If you receive too much (overdose)

As your doctor will supervise how much Zeldox IM you are given, you are unlikely to have an overdose.

If you are given too much Zeldox IM, you may feel slightly drowsy and your speech may be slurred.

You may also experience high and low blood pressure, diarrhoea and a fast heart rate. Your lungs might fail to breathe properly which can result in a build-up of carbon dioxide in the body

If you think you have been given too much Zeldox IM:

  • tell your doctor or nurse immediately, or
  • telephone the Poisons Information Centre on 131 126.

Side effects

This medicine has been prescribed to help you, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

It is important to tell your doctor or nurse as soon as possible if you do not feel well while you are being treated with Zeldox IM.

Zeldox may also cause falls resulting in fractures or other injuries in some people.

Other side effects not listed below may also occur in some people.

Tell your doctor if...

The following list shows common side effects of Zeldox IM. Some of these side effects may affect up to 1 in 10 people, whereas others are less common.

Tell your doctor or nurse if you notice any of the following physical problems and they worry you.

  • weakness or loss of strength
  • palpitations or a fast heart rate
  • dizziness on standing up, especially when getting up from a sitting or lying position
  • pain or irritation where the injection is given
  • headache
  • constipation
  • diarrhoea
  • dry mouth
  • feeling sick (nausea)
  • vomiting
  • loss of appetite
  • difficulties breathing
  • difficulties speaking
  • excessive sweating
  • flushing
  • muscle stiffness
  • involuntary muscle spasms
  • blurred vision
  • male sexual dysfunction.

Tell your doctor or nurse if you notice any of the following mental or emotional problems and they worry you:

  • drowsiness or sleepiness
  • trouble sleeping
  • restlessness or difficulty sitting still
  • dizziness, blackouts or feeling faint
  • anxiety or agitation
  • loss of control of your bladder
  • unusual secretion of breast milk.

Tell your doctor or pharmacist if you have a persistent painful erection of the penis without sexual arousal.

Tell your doctor immediately if...

The following list includes serious side effects which may require medical attention.

Do not be alarmed as you may not experience any of them.

Tell your doctor or nurse immediately if you notice:

  • any worm-like movements of the tongue
  • any other uncontrolled movements of the tongue, mouth, cheeks or jaw
  • any uncontrolled movements spreading to the arms and legs
  • sleepwalking
  • eating during sleepwalking
  • breathing stops and starts while sleeping. Symptoms can be loud or frequent snoring, silent pauses in breathing, choking or gasping sounds.

These are symptoms of a condition called tardive dyskinesia. Tardive dyskinesia is more likely in people who have been given Zeldox IM or taking other antipsychotic medications for a long time. If detected early, it is usually reversible. Your doctor will decide whether to lower your dose or stop the medicine completely.

Get emergency attention if...

The following list contains very serious side effects. These symptoms can also sometimes happen after you stop Zeldox IM treatment. You may need urgent medical attention or hospitalisation.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • convulsions, fits or seizures
  • trembling and shaking of the hands and fingers
  • shuffling walk and stiffness of the arms and legs
  • sudden uncontrollable muscle spasms in the eyes, head, neck and body
  • sudden signs of allergy - including skin rash, itching or hives, swelling of the face, lips or tongue, shortness of breath or difficulty breathing (symptoms resembling a condition called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS))
  • pain and swelling in the large veins of your legs or hip
  • sharp chest pain, shortness of breath or and coughing up blood

Experience symptoms of a condition called Neuroleptic Malignant Syndrome (NMS) which include:

  • high fever
  • fast breathing
  • stiff muscles
  • confusion, drowsiness or sleepiness.

Talk to your doctor or mental health professional if you have thoughts or talk about death, suicide or self-harm. These may be signs of changes or worsening in your mental illness.

Product description

What it looks like

Zeldox IM is supplied to the hospital as a sterile powder for injection, with an ampoule of Water for Injections.

The hospital will mix the Zeldox IM and Water for Injections to produce a solution containing ziprasidone 20 mg/mL.

Ingredients

Zeldox IM contains the active ingredient ziprasidone.

The inactive ingredients are:

  • sulfobutyl betadex sodium (SBECD)
  • Water for Injections.

Supplier

Zeldox IM is supplied in Australia by:

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Australian registration number

AUST R 154458.

This leaflet was prepared in November 2022.

ZELDOX IM® is a Viatris company trade mark

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Published by MIMS January 2023

BRAND INFORMATION

Brand name

Zeldox IM

Active ingredient

Ziprasidone

Schedule

S4

 

1 Name of Medicine

Ziprasidone mesilate.

2 Qualitative and Quantitative Composition

Zeldox IM contains ziprasidone (as mesilate). When reconstituted with 1.2 mL Water for Injections, each vial contains 20 mg ziprasidone and 294 mg of the inactive ingredient, sulfobutyl betadex sodium (SBECD) per mL.
An ampoule containing 1.2 mL of Sterile Water for Injections Ph. Eur. is also supplied for reconstitution purposes.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zeldox IM is presented as a sterile lyophilised powder in a single dose vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Acute treatment and short-term management of agitation and disturbed behaviour in patients with schizophrenia and related psychoses when oral therapy is not appropriate.

4.2 Dose and Method of Administration

For intramuscular use only.
Do not administer intravenously.
The recommended dose is 10 to 20 mg administered as required up to a maximum dose of 40 mg per day. Doses of 10 mg may be administered every 2 hours, doses of 20 mg may be administered every 4 hours up to a maximum of 40 mg/day.
Intramuscular administration of ziprasidone for more than three consecutive days has not been studied.
If therapy is indicated, oral ziprasidone hydrochloride capsules, up to 80 mg twice daily, should replace the intramuscular administration as soon as possible.

Dosage adjustment in renal impairment.

As SBECD is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment).

Dosage adjustment in hepatic impairment.

In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhoses, the serum concentrations after oral administration were 30% higher and the terminal half-life was about two hours longer than in normal patients.
In patients with mild to moderate hepatic insufficiency, lower doses should be considered.
A toxicity study in dogs showed intrahepatic cholestasis and elevation of serum ALT and alkaline phosphatase at oral ziprasidone doses producing exposure (plasma AUC) about twice the maximal clinical exposure.
There is a lack of experience in patients with severe hepatic insufficiency and ziprasidone should be used with caution in this group (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).

Dosage adjustment in the elderly.

Ziprasidone intramuscular has not been systematically evaluated in elderly patients (65 years and over).

Dosage adjustment in patients who smoke.

No dosage adjustment is required in patients who smoke (see Section 5.2 Pharmacokinetic Properties, Special populations, Smoking).

Preparation for administration.

Zeldox IM should only be administered by intramuscular injection. This product is for single use in one patient only. Vials require reconstitution prior to administration, any unused portion should be discarded.
Add 1.2 mL of the supplied sterile water for injections to the vial and shake vigorously until all the drug is dissolved. Each mL of reconstituted solution contains 20 mg ziprasidone. Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final solution. This medicinal product must not be mixed with other medicinal products or solvents other than sterile water for injections.
To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, store at 2-8°C (Refrigerate. Do not freeze) for not more than 24 hours.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Due to the viscosity of the solution, approximately 0.5 mL of the reconstituted solution remains in the vial following administration.

4.3 Contraindications

Known hypersensitivity to any ingredient of the product.
Recent acute myocardial infarction.
Uncompensated heart failure.
Conditions with a potential to increase QT interval:
QT interval prolongation or history of QT prolongation;
congenital long QT syndrome;
use with other drugs known to increase the QT interval;
arrhythmias treated with class IA and III antiarrhythmic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

QT prolongation and proarrhythmias.

Ziprasidone causes a mild to moderate prolongation of the QT interval. A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. The mean change in QTc from baseline was calculated using a sample based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for oral ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine.
In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was coadministered with the appropriate inhibitor(s) of the CYP450 metabolism specific for each drug. The effect of oral ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).
In placebo controlled schizophrenia trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In schizophrenia clinical trials with ziprasidone, the electrocardiograms of 3/3266 (0.1%) patients who received ziprasidone and 1/538 (0.2%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone treated patients, neither case suggested a role of ziprasidone.
A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated, using a sample based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec and 12.8 msec, following the first and second injections, respectively. The mean increase in QTc from baseline for haloperidol was 6.0 msec and 14.7 msec, following the first and second injections, injection respectively. No patients had a QTc interval exceeding 500 msec.
Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. There have been rare postmarketing reports of torsade de pointes in patients with multiple confounding risk factors taking ziprasidone. A causal relationship between torsade de pointes and ziprasidone has not been established.
As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. Experience with ziprasidone has not revealed an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo.
Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) electrolyte imbalances (especially hypokalaemia or hypomagnesaemia); (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval (see Section 4.3 Contraindications).
It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalaemia in particular, have baseline serum potassium and magnesium measurements. Hypokalaemia may result from diuretic therapy, diarrhoea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness (see Section 4.3 Contraindications). Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements > 500 msec.
For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, e.g. dizziness, palpitations, syncope or seizures, the prescriber should initiate further evaluation, e.g. Holter monitoring, may be useful. The possibility of a malignant cardiac arrhythmia should also be considered and a cardiac evaluation including an ECG should be performed.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with ziprasidone and preventive measures undertaken.

Neuroleptic malignant syndrome (NMS).

Neuroleptic malignant syndrome, a potentially fatal complex, has been reported in association with antipsychotic drugs, including ziprasidone. The clinical manifestations are hyperthermia, muscle rigidity, altered mental status and signs of autonomic instability such as irregular pulse and blood pressure, tachycardia, cardiac arrhythmias and diaphoresis. Additional features may include elevated creatine phosphokinase, rhabdomyolysis and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs, including ziprasidone, should be discontinued.

Severe cutaneous adverse reactions.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with ziprasidone exposure. DRESS consists of a combination of: a) three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy; and b) one or more systemic complications (such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis).
Other severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, have also been reported with ziprasidone exposure. SCARs are sometimes fatal and ziprasidone should be discontinued if SCARs occur.

Tardive dyskinesia.

In fixed dose, placebo controlled trials, in patients with schizophrenia, of up to six weeks duration, the incidence of treatment emergent tardive dyskinesia was comparable in patients receiving oral ziprasidone and placebo and lower than patients treated with active comparator (0.4% ziprasidone, 1.2% haloperidol and 0.7% placebo). In a 52 week, placebo controlled trial in patients with schizophrenia, only one out of 219 patients treated with oral ziprasidone experienced tardive dyskinesia.
As with other antipsychotic agents, the risk of tardive dyskinesia and other tardive extrapyramidal syndromes may increase with long-term exposure and therefore if signs or symptoms of tardive dyskinesia appear in a patient on ziprasidone, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Falls.

Antipsychotic drugs (which includes ziprasidone) may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, a fall risk assessment should be completed when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Cardiovascular disease.

Patients with cardiovascular disease have not been included in clinical trials in sufficient numbers. Thus, the safe use of the intramuscular product has not been established (see Section 4.3 Contraindications).

Blood pressure.

Dizziness, tachycardia and postural hypotension are not unusual in patients following intramuscular administration of ziprasidone. Single cases of hypertension have also been reported. Caution should be exercised, particularly in ambulatory patients.
Oral ziprasidone may induce orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, especially during the initial dose titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 0.6% of the patients treated with oral ziprasidone in schizophrenia clinical trials.
Ziprasidone should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease or conditions which would predispose patients to hypotension.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder, and close supervision of high risk patients should accompany therapy. Prescriptions for the oral preparation of ziprasidone should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Akathisia.

The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

CNS drugs and alcohol.

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting agents, including alcohol and drugs acting on the dopaminergic and serotonergic systems.
Since there is no experience regarding the safety of administering ziprasidone intramuscular to schizophrenic patients already taking oral ziprasidone, the practice of coadministration is not recommended.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycaemia or diabetes in patients treated with ziprasidone. Although fewer patients have been treated with ziprasidone, it is not known if this more limited experience is the sole reason for the paucity of such reports. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia related adverse events is not completely understood. However, epidemiological studies, which did not include ziprasidone, suggest an increased risk of treatment emergent hyperglycaemia related adverse events in patients treated with atypical antipsychotics included in these studies. Because ziprasidone was not marketed at the time these studies were performed, it is not known if ziprasidone is associated with this increased risk. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect medicine.

Rash.

In premarketing schizophrenia trials with oral ziprasidone, about 5% of patients developed rash and/or urticaria, with discontinuation of treatment in about one sixth of these cases. The occurrence of rash was related to dose of oral ziprasidone, although the finding might also be explained by the longer exposure time in the higher dose patients. Several patients with rash had signs and symptoms of associated systemic illness, e.g. elevated WBCs. Most patients improved promptly with adjunctive treatment with antihistamines or steroids and/or upon discontinuation of ziprasidone, and all patients experiencing these events were reported to recover completely. Upon appearance of rash for which an alternative aetiology cannot be identified, ziprasidone should be discontinued.

Hyperprolactinaemia.

As with other drugs that antagonise dopamine D2 receptors, oral ziprasidone elevates prolactin levels in humans. Increased prolactin levels were also observed in animal studies with this compound, and were associated with an increase in mammary gland neoplasia in mice; a similar effect was not observed in rats (see Section 5.3 Preclinical Safety Data, Carcinogenicity). Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
Although disturbances such as galactorrhoea, amenorrhoea, gynaecomastia, and impotence have been reported with prolactin elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. Long standing hyperprolactinaemia when associated with hypogonadism may lead to decreased bone density.

Seizures.

As with other antipsychotics, caution is recommended when treating patients with a history of seizures.

Increased mortality in elderly patients with dementia related psychosis.

Elderly patients with dementia related psychosis treated with antipsychotic drugs are at an increased risk of death and/or potentially, cerebrovascular adverse events compared with placebo. Analyses of seventeen oral placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug treated patients of between 1.6 to 1.7 times that seen in placebo treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Ziprasidone is not approved for the treatment of elderly patients with dementia related psychosis.

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with antipsychotics, such as ziprasidone, with or without prior history of sleep apnoea, and with or without concomitant weight-gain. Caution should be taken in patients who have a history of or are at risk for sleep apnoea, or who are concomitantly using central nervous system depressants.

Postmarketing reports of mortality.

As with other IM antipsychotics, fatalities with the use of ziprasidone IM, generally in patients with multiple confounding risk factors, have been reported. Although a causal relationship has not been established, ziprasidone IM should be used with caution.

Priapism.

Cases of priapism have been reported with antipsychotic use, including ziprasidone.

Use in hepatic impairment.

In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhoses, the serum concentrations after oral administration were 30% higher and the terminal half-life was about two hours longer than in normal patients.
In patients with mild to moderate hepatic insufficiency, lower doses should be considered.
A toxicity study in dogs showed intrahepatic cholestasis and elevation of serum ALT and alkaline phosphatase at oral ziprasidone doses producing exposure (plasma AUC) about twice the maximal clinical exposure.
There is a lack of experience in patients with severe hepatic insufficiency and ziprasidone should be used with caution in this group (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).

Use in renal impairment.

As SBECD is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment).

Use in the elderly.

Ziprasidone intramuscular injection has not been systematically evaluated in elderly patients (65 years and over).

Paediatric use.

Ziprasidone intramuscular injection has not been systematically evaluated in subjects under 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

All interaction studies have been conducted with oral ziprasidone.

Effect of ziprasidone on other medicines.

Using human liver microsomes, ziprasidone demonstrated no inhibitory effect on CYP1A2, CYP2C9 or CYP2C19. The concentration of ziprasidone required to inhibit CYP2D6 and CYP3A4 in vitro is at least 1000-fold higher than the free concentration that can be expected in vivo. Although the clinical relevance of this finding is uncertain, ziprasidone is unlikely to cause clinically important drug interactions mediated by these enzymes.

QTc prolongation.

As with other antipsychotic agents, there is an increased potential of QTc prolongation in the presence of type IA and IIIA antiarrhythmics. Class IA and III antiarrhythmics that prolong the QT/QTc interval greater than 500 msec have been associated with the occurrence of torsade de pointes and with sudden unexplained death.
Coadministration with the potent CYP3A4 inhibitor, ketoconazole, did not affect QTc, when compared to ziprasidone alone (see Section 4.3 Contraindications).

Dextromethorphan.

The pharmacokinetics and metabolism of dextromethorphan, a CYP2D6 substrate, were unaffected by ziprasidone.

Oral contraceptives.

Ziprasidone administration at a dose of 20 mg twice daily resulted in no significant change to the pharmacokinetics of estrogen (ethinyl estradiol 0.03 mg, a CYP3A4 substrate) or progesterone components (levonorgestrel 0.15 mg).

Lithium.

Coadministration of ziprasidone at a dose of 40 mg twice daily had no effect on the pharmacokinetics of lithium at a dose of 450 mg twice daily for 7 days. In this study, steady-state lithium concentrations prior to coadministration of ziprasidone were 0.49 mEq/L.
As ziprasidone and lithium are associated with cardiac conduction changes, the combination may pose a potential for pharmacodynamic interaction, including arrhythmias. While there have been no reports of clinically significant QTc increases in clinical trials of adjunctive therapy involving ziprasidone and lithium, caution should be exercised in prescribing the two drugs together.

Protein binding.

Ziprasidone extensively binds to plasma proteins. The in vitro plasma protein binding of ziprasidone was not altered by warfarin or propranolol, two highly protein bound drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus, the potential for drug interactions with ziprasidone due to displacement is unlikely.

Effects of other medicines on ziprasidone.

CYP3A4 inhibitors.

Coadministration of potent CYP3A4 inhibitors has the potential of increasing ziprasidone serum concentrations. The clinical importance of this potential has not been clearly defined.
In vitro data indicate that ziprasidone is a P-glycoprotein (P-gp) substrate. The in vivo relevance is unknown.
Ketoconazole, a potent CYP3A4 inhibitor (400 mg/day), increased the serum concentrations of ziprasidone by approximately 35% to 40% when compared to ziprasidone alone. The serum concentration of S-methyl-dihydroziprasidone, at the expected Tmax of ziprasidone, was increased by 55% during ketoconazole treatment. No additional QTc prolongation was observed.
Cimetidine, a CYP3A4 inhibitor, at a dose of 800 mg QD for 2 days did not significantly alter the pharmacokinetics of ziprasidone.

CYP3A4 inducers.

Coadministration with inducers of CYP3A4 and P-gp such as carbamazepine, rifampin and St. John's wort (Hypericum perforatum) could cause decreased concentrations of ziprasidone.
Carbamazepine, a CYP3A4 inducer, produced a decrease in AUC (36%) and Cmax (25%) of ziprasidone.

CNS drugs.

Given the primary CNS effects of ziprasidone, caution should be used when it is taken in combination with other centrally acting drugs. As it exhibits in vitro dopamine antagonism, ziprasidone may antagonise the effects of direct and indirect dopamine agonists.

Antacid.

Multiple doses of aluminium and magnesium containing antacid did not affect the pharmacokinetics of ziprasidone.

Other.

In addition, pharmacokinetic screening of patients in clinical trials has not revealed any evidence of clinically significant interactions with benztropine, propranolol or lorazepam.
Ziprasidone has not been studied for drug interaction with valproate or lamotrigine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no adequate and well-controlled studies in women and men exposed to ziprasidone.
Contraception - Women of childbearing potential receiving ziprasidone should be advised to use an appropriate method of contraception.
Ziprasidone hydrochloride was shown to increase time to copulation in rats at oral doses of 10 to 160 mg/kg/day (0.5 to 8 times the oral MRHD on a mg/m2 basis). Fertility was impaired in rats dosed orally with ziprasidone hydrochloride 160 mg/kg/day, with a no effect dose level of 40 mg/kg/day (2 times the MRHD on a mg/m2 basis). The effect appeared to be in the female since the length of the oestrous cycle was increased, a pharmacologic effect of dopamine antagonists in rats. Increased oestrous cycle length was observed in female rats treated intramuscularly with ziprasidone mesilate 2 mg/kg/day or greater (less than the clinical exposure based on AUC). Fertility was not impaired when males were given oral ziprasidone hydrochloride 160 mg/kg/day or intramuscular ziprasidone mesilate 20 mg/kg/day (6 times the clinical exposure based on AUC) and mated with untreated females, and there were no treatment related findings in the testes of male rats given ziprasidone hydrochloride 200 mg/kg/day orally (11 times the MRHD on a mg/m2 basis).
(Category C)
In animal studies ziprasidone hydrochloride crossed the placenta and demonstrated developmental toxicity, including possible teratogenic effects at doses/ exposures similar to clinical doses/ exposures. When ziprasidone hydrochloride was administered to pregnant rabbits during the period of organogenesis, there was an increased incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular malformations and kidney alterations) at an oral dose of 30 mg/kg/day (3 times the MRHD on a mg/m2 basis), and an increased incidence of vertebral arches fused to the pelvis after intramuscular ziprasidone mesilate at 5 mg/kg/day or greater (twice the clinical exposure based on AUC). There was no evidence to suggest that these developmental effects were secondary to maternal toxicity. The developmental no effect doses were 10 mg/kg/day orally (similar to the MRHD on a mg/m2 basis) and 1 mg/kg/day intramuscular ziprasidone mesilate (less than clinical exposure based on AUC). Studies in rats have not shown adverse effects on embryofetal development, other than those associated with maternal toxicity, when ziprasidone hydrochloride was administered during the period of organogenesis at oral doses up to 160 mg/kg/day (8 times the MRHD on a mg/m2 basis) or intramuscular ziprasidone mesilate up to 40 mg/kg/day (11-fold the clinical exposure based on AUC).
The incidence of stillbirths was increased when ziprasidone was administered at oral doses of ziprasidone hydrochloride of 10 mg/kg/day or greater to rats throughout gestation or intramuscular doses of ziprasidone mesilate of 2 mg/kg/day or greater. Estimated systemic exposure at the no effect dose for perinatal mortality (5 mg/kg/day or 2 mg/kg/day for oral and intramuscular administration, respectively) was less than that in humans at the maximum recommended dose. Offspring showed increased postnatal mortality, suppression of growth and delayed development when ziprasidone was administered to rats orally during gestation and lactation at 40 mg/kg/day (2 times the MRHD on a mg/m2 basis) or intramuscularly at 6 mg/kg/day or greater (2 times the clinical exposure based on AUC). The estimated systemic exposure in dams at the no effect dose for offspring (5 mg/kg/day orally or 2 mg/kg/day intramuscularly) was less than that in humans at the MRHD.
There are no adequate and well controlled clinical trials in pregnant women. Women of childbearing potential receiving ziprasidone should therefore be advised to use an appropriate method of contraception. As human experience is limited, administration of ziprasidone is not recommended during pregnancy.

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including ziprasidone) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarketing reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring.
Ziprasidone should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
 There are no adequate and well-controlled studies in lactating women. Limited data indicate that ziprasidone and its active metabolites are excreted into breast milk at very low levels. Offspring showed increased postnatal mortality, suppression of growth and delayed development when ziprasidone was administered to rats orally during gestation and lactation at 40 mg/kg/day (2 times the MRHD on a mg/m2 basis) or intramuscularly at 6 mg/kg/day or greater (2 times the clinical exposure based on AUC). The estimated systemic exposure in dams at the no effect dose for offspring (5 mg/kg/day orally or 2 mg/kg/day intramuscularly) was less than that in humans at the MRHD. Patients should be advised not to breast feed if they are taking ziprasidone.

4.7 Effects on Ability to Drive and Use Machines

As with other psychoactive medicines, ziprasidone may cause somnolence. Patients likely to drive or operate other machines should therefore be cautioned appropriately.

4.8 Adverse Effects (Undesirable Effects)

Ziprasidone intramuscular.

Table 1 contains adverse events with possible, probable or unknown relationship to ziprasidone in phase 2/3 trials. The most common reactions were nausea, sedation, dizziness, injection site pain, headache and somnolence.
All adverse reactions are listed by class and frequency (very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100) and rare (< 1/1000)).
The adverse reactions listed below may also be associated with the underlying disease and/or concomitant medications.
The most common cardiovascular adverse events reported from fixed dose clinical trials with intramuscular ziprasidone were: dizziness (10 mg: 11%; 20 mg: 12%), tachycardia (10 mg: 4%; 20 mg: 4%) and postural dizziness (10 mg: 2%; 20 mg: 2%), orthostatic hypotension (20 mg: 5%) and hypotension (10 mg: 2%).
In premarketing fixed dose clinical trials with ziprasidone intramuscular injection, increased blood pressure and hypertension were observed in 2.2% of patients receiving 10 mg and increased blood pressure was observed in 2.8% of patients receiving 20 mg.
Table 2 contains treatment emergent, all causality adverse events with an incidence of ≥ 1% for ziprasidone IM and haloperidol IM from two clinical studies.

Ziprasidone oral.

Table 3 contains treatment emergent adverse events that occurred at an incidence of greater than or equal to 1% in monotherapy double blind placebo controlled studies in patients with bipolar mania and short-term double blind, placebo controlled studies in patients with schizophrenia.
All adverse reactions are listed by class and frequency: very common (> 10%), common (1% to 10%), uncommon (0.1% to 1%) and rare (< 0.1%).

General disorders and administration site conditions.

Uncommon: gait disturbance, thirst, malaise. Rare: chest pain, feeling hot, pyrexia, sluggishness.

Cardiac disorders.

Uncommon: bundle branch block right, palpitation.

Gastrointestinal disorders.

Uncommon: dysphagia, flatulence, gastritis. Rare: gastro-oesophageal reflux, diarrhoea.

Blood and lymphatic system disorders.

Rare: lymphopenia.

Ear and labyrinth disorders.

Uncommon: tinnitus, vertigo. Rare: ear pain, vertigo positional.

Eye disorders.

Common: visual impairment. Uncommon: photophobia, oculogyric crisis. Rare: amblyopia, eye pruritus.

Investigations.

Uncommon: hepatic enzyme increased, heart rate increased, electrocardiogram QT interval prolonged. Rare: blood lactate dehydrogenase increased, body temperature increased, eosinophil count increased, eosinophil count abnormal, hypocalcaemia, liver function test abnormal, heart rate increased.

Infections and infestations.

Uncommon: rhinitis.

Metabolism and nutrition disorders.

Uncommon: increased appetite.

Musculoskeletal and connective tissue disorders.

Uncommon: joint stiffness, muscle spasms, pain in extremity, torticollis. Rare: arthropathy, musculoskeletal discomfort, trismus.

Nervous system disorders.

Common: tardive dyskinesia, hypertonia. Uncommon: ataxia, bradykinesia, cogwheel rigidity, disturbance in attention, dizziness postural, drooling, dysarthria, generalised tonic clonic seizures, hypokinesia, hypersomnia, hypoaesthesia, lethargy, paraesthesia, hyperkinesia, speech disorder. Rare: akinesia, paresis, restless legs syndrome.

Psychiatric disorders.

Common: anxiety, agitation. Uncommon: nightmare, nervousness, libido decreased. Rare: anorgasmia, bradyphrenia, flat affect, panic attack, somnambulism.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, oropharyngeal pain, throat tightness. Rare: hiccups, laryngospasm.

Renal and urinary disorders.

Uncommon: dysuria, urinary incontinence, urinary hesitation. Rare: urinary retention.

Reproductive system and breast disorders.

Common: male sexual dysfunction. Uncommon: galactorrhoea, gynaecomastia, amenorrhea.

Skin and subcutaneous tissue disorders.

Common: rash. Uncommon: acne, rash maculopapular, urticaria. Rare: alopecia, dermatitis allergic, erythema, psoriasis, skin irritation, swelling face, rash papular.
Other findings for ziprasidone oral.

Extrapyramidal symptoms (EPS).

In double blind active controlled clinical trials in patients with schizophrenia, the Movement Disorder Burden Scale, a composite measure of EPS, was statistically significantly (p < 0.05) in favour of ziprasidone versus haloperidol and risperidone. In addition the reported incidence of akathisia and use of anticholinergic drugs was greater in the haloperidol and risperidone groups relative to ziprasidone. The incidence of reported EPS for ziprasidone treated patients in the short-term, placebo controlled trials was 5% vs. 1% for placebo.

Bodyweight.

The incidence of bodyweight gain, recorded as an adverse event in short-term 4 and 6 week, fixed dose, placebo controlled schizophrenia trials, was low and identical in ziprasidone treated and placebo treated patients (both 0.4%). There was a small increase in median weight in ziprasidone treated patients (0.5 kg) but not in placebo treated patients.
In a one year placebo controlled schizophrenia study a median weight loss of 1-3 kg was observed in ziprasidone treated patients compared to a 3 kg median loss in placebo treated patients.

QT interval.

In schizophrenia clinical trials with oral ziprasidone, an increase of 30 to 60 msec was seen in 12.3% (976/7941) of ECG tracings from ziprasidone treated and 7.5% (83/975) of ECG tracings from placebo treated patients. A prolongation of > 60 msec was seen in 1.6% (128/7941) and 1.2% (12/975) of tracings from ziprasidone and placebo treated patients, respectively. The incidence of QTc interval prolongation above 500 msec was 3 in a total of 3266 (0.1%) in ziprasidone treated patients and 1 in a total of 538 (0.2%) in placebo treated patients.

Dose dependency of adverse events in short-term, placebo controlled trials.

An analysis for dose response in this 4 study pool revealed an apparent relation of adverse event to dose for the following events: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.

Vital sign changes.

Ziprasidone is associated with orthostatic hypotension (see Section 4.4 Special Warnings and Precautions for Use).

Prolactin levels.

There were only transient prolactin increases seen during chronic dosing with ziprasidone.
In phase 2/3 clinical trials, prolactin levels in patients treated with ziprasidone were sometimes elevated (12%) compared with the placebo group (3%), but potential clinical manifestation (e.g. gynaecomastia 0.1%) were rare. In most patients, levels returned to normal ranges without cessation of treatment. In the clinical studies the degree and incidence of prolactin elevation was lower in ziprasidone patients than in patients treated with haloperidol (29%) or risperidone (60%).

Physical and psychological dependence.

Ziprasidone has not been systemically studied in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug seeking behaviour, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which ziprasidone will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse and such patients should be observed closely for signs of ziprasidone misuse or abuse (e.g. development of tolerance, increases in dose, drug seeking behaviour).

Postmarketing experience.

The following adverse events have been reported with the oral and/or intramuscular formulation during postmarketing experience.

Immune system disorders.

Hypersensitivity.

Investigations.

Weight decreased, weight increased.

Endocrine disorders.

Hyperprolactinaemia.

Psychiatric disorders.

Mania/ hypomania, insomnia, somnambulism, sleep-related eating disorder.

Respiratory, thoracic and mediastinal disorders.

Sleep apnoea.

Nervous system disorders.

Syncope, facial droop, neuroleptic malignant syndrome (see Section 4.4 Special Warnings and Precautions for Use); serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia, dystonia, sedation.

Cardiac disorders.

Tachycardia, torsades de pointes (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Orthostatic hypotension, hypotension, embolism venous (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Dysphagia, tongue oedema, vomiting.

Skin and subcutaneous tissue disorders.

Angioedema, rash, drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders.

Enuresis, urinary incontinence.

Reproductive system and breast disorders.

Galactorrhoea, priapism.

General disorders and administration site conditions.

Fatigue.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Experience with oral ziprasidone in overdosage is limited. In overdose cases in general, the most commonly reported symptoms are extrapyramidal symptoms, somnolence, tremor and anxiety. Hypertension, hypotension, diarrhoea, tachycardia and prolongation of the QTc and QRS intervals have also been reported. Respiratory depression may occur following massive overdoses due to CNS depression. The largest confirmed single ingestion is 12,800 mg. In this case, extrapyramidal symptoms and a QTc interval of 446 msec (with no cardiac sequelae) were reported.

Treatment of overdosage.

In cases of suspected overdose, the possibility of multiple drug involvement should be considered. There is no specific antidote to ziprasidone. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation and oxygenation. Monitor respiratory function, vital signs and blood pressure. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT prolonging effects that might be additive to those of ziprasidone.
Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids. If sympathomimetic agents are used for vascular support, adrenaline and dopamine should not be used, since beta stimulation combined with α1-antagonism associated with ziprasidone may worsen hypotension. Monitor for CNS depression, seizures and extrapyramidal reactions. In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Monitor liver function tests as increased serum liver enzymes may result following overdose.
The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis, therefore emesis is not recommended. Administration of activated charcoal should be considered and is most effective when administered within 1 hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Given the high protein binding of ziprasidone haemodialysis is unlikely to be beneficial in the treatment of overdose. Close medical monitoring and supervision should continue until the patient recovers.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Receptor binding studies.

Ziprasidone exhibited high in vitro binding affinity for the dopamine D2 and D3, the serotonin 5HT2A, 5HT2C, 5HT1A and 5HT1D and α1-adrenergic receptors (KiS of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nanomolar, respectively) and moderate affinity for the histamine H1 receptor (Ki = 47 nanomolar). Ziprasidone functioned as an antagonist at the D2, 5HT2A, and 5HT1D receptors, and as an agonist at the 5HT1A receptor. Ziprasidone inhibited synaptic reuptake of serotonin and noradrenaline. No appreciable affinity was exhibited for the other receptor/ binding sites tested, including the cholinergic muscarinic receptor (IC50 > 1 micromolar).
The mechanism of action of ziprasidone in the acute control of the agitated psychotic patient is unknown. The mechanism of action of ziprasidone in schizophrenia, as with other drugs having efficacy in schizophrenia, is also unknown; however, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism.
Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

Receptor functional studies.

Ziprasidone has been shown to be an antagonist at both serotonin type 2A (5HT2A) and dopamine type 2 (D2) receptors. It is proposed that the antipsychotic activity is mediated, in part, through this combination of antagonist activities.
Ziprasidone is also a potent antagonist at 5HT2C and 5HT1D receptors, a potent agonist at the 5HT1A receptor and inhibits neuronal reuptake of noradrenaline and serotonin.

Positron emission tomography studies.

Receptor blockade, 12 hours after a single oral dose of 40 mg, was greater than 80% for 5HT2A and greater than 50% for D2 using positron emission tomography (PET).

Clinical trials.

Two pivotal, single blinded, active comparator trials were conducted to compare the effects of ziprasidone IM to IM haloperidol in patients with acute exacerbation of schizophrenia or schizoaffective disorder.
A multicentre, parallel group study (1) compared ziprasidone IM (N = 429) and IM haloperidol (N = 138) administered for 1-3 days, followed by oral ziprasidone and haloperidol for another 6 weeks. The IM dosing was 10 mg or 20 mg ziprasidone or 2.5 mg or 5 mg haloperidol, administered at least twice. During the subsequent oral administration, the total daily ziprasidone dose was 80-160 mg and the daily haloperidol dose was 5-20 mg/day.
The other multicentre, parallel group study (2) compared IM ziprasidone (N = 130) and IM haloperidol (N = 122) administered for 1-3 days, followed by oral ziprasidone and haloperidol for another 6 weeks. The IM and oral dosing regimens for ziprasidone and haloperidol are the same as the regimens in the other study.
In both studies, male and female subjects aged 18-70 years at the time of randomisation were eligible for inclusion in this study. Subjects had to meet diagnostic and statistical manual (of mental disorders) (DSM)-IV criteria for schizophrenia or schizoaffective disorder. Subjects entering hospital (or inpatients transferring to a higher dependency unit) within the previous seven days because of acute exacerbation of psychotic symptoms were included. Subjects had to have a minimum score of 40 on the Brief Psychiatric Rating Scale (BPRS) scale (1-7) and agree to receive intramuscular medication for 1-3 days (at least two administrations). Subjects were excluded if they were receiving concurrent treatment with antipsychotic agents at randomisation (within 12 hours prior to randomisation); for depot agents a period of two weeks or one cycle, whichever was the longer, had to occur between last administration and randomisation.
The results for the BPRS from these two studies are presented in Table 4; responders were those patients with a Clinical Global Impression-Improvement (CGI-I) score of 1, 2 or 3 (equates to very much improved to improved).
Ziprasidone was superior to haloperidol (LOCF on the ITT analysis set) in the change from baseline in the total BPRS score at the end of the IM phase in the first study and comparable to haloperidol in the second study. Ziprasidone was also comparable to haloperidol with respect to responder rates at both the end of the IM and the end of the IM/oral phase in both studies.

Results of a large postmarketing safety study (Zodiac study).

A randomised postapproval study of 18,239 patients with observational follow-up for 1 year was conducted to determine whether ziprasidone is associated with an increased risk of nonsuicide mortality in patients with schizophrenia, compared to olanzapine. This study, which was conducted in naturalistic clinical practice settings, showed no significant difference in its primary endpoint of the rate of nonsuicide mortality between ziprasidone and olanzapine treatments (risk ratio 1.02; 95% CI 0.76-1.39). All cause mortality also did not differ between the two treatment groups (risk ratio 1.01; 95% CI 0.77-1.33).

5.2 Pharmacokinetic Properties

Absorption.

The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 60 minutes postdose. Exposure increases in a dose related manner and following three days of intramuscular dosing, little accumulation is observed.

Distribution.

Ziprasidone is greater than 99% protein bound, binding primarily to albumin and α1-acid glycoprotein. Twice daily dosing generally leads to attainment of steady state within one to three days. Systemic exposures at steady state are related to dose. Ziprasidone has a volume of distribution of approximately 1.1 L/kg when administered intravenously.

Metabolism.

Ziprasidone is extensively metabolised after oral administration with only a small amount excreted in the urine (< 1%) or faeces (< 4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulphoxide, BITP sulphone, ziprasidone sulphoxide and S-methyl-dihydroziprasidone. Approximately 20% of the dose is excreted in the urine, with approximately 66% being eliminated in the faeces. Unchanged ziprasidone represents about 44% of total drug related concentration in serum.
In vitro studies indicate that CYP3A4 is the major cytochrome catalysing the oxidative metabolism of ziprasidone with some potential contribution from CYP1A2. S-methyl-dihydroziprasidone is generated in two steps catalysed by aldehyde oxidase and thiol methyltransferase.
Ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties which may predict a QTc prolonging effect. S-methyl-dihydroziprasidone is mainly eliminated by biliary excretion and CYP3A4 catalysed metabolism. The sulphoxide is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
After ziprasidone is administered intramuscularly, approximately 20% of the dose is excreted in urine and approximately 66% is eliminated in faeces.

Excretion.

The mean terminal phase half-life after multiple oral dosing in normal volunteers and schizophrenic patients is between 6 and 10 hours, with a range of individual values from 3 to 18 hours.
The mean terminal half-life on the third day of dosing ranged from 8 to 10 hours. The mean terminal half-life of ziprasidone after intravenous administration is 3 hours. Mean clearance of ziprasidone administered intravenously is 5 mL/min/kg.
The mean terminal half-life of ziprasidone after intramuscular administration of single doses ranges from 2 to 5 hours.

Special populations.

Age and gender.

No clinically significant age or gender differences in the pharmacokinetics were observed following oral administration.

Race.

No specific pharmacokinetic study was conducted to investigate the effects of race. Population pharmacokinetic evaluation has revealed no evidence of clinically significant race related differences in the pharmacokinetics of oral ziprasidone. Dosage modifications for race are, therefore, not recommended.

Smoking.

Pharmacokinetic screening of patients treated orally has not revealed any significant pharmacokinetic differences between smokers and nonsmokers.

Renal impairment.

Because ziprasidone is highly metabolised, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a major impact on the pharmacokinetics of ziprasidone. The pharmacokinetics of oral ziprasidone following 8 days of 20 mg twice daily dosing were similar among subjects with varying degrees of renal impairment (n = 27), and subjects with normal renal function, indicating that dosage adjustment based upon the degree of renal impairment is not required. Ziprasidone is not removed by haemodialysis.
No marked differences in the pharmacokinetics of oral ziprasidone have been observed in patients with decreased kidney function (creatinine clearance > 10 mL/min). It is unknown whether serum concentrations of the metabolites are increased in these patients.
As SBECD is cleared by renal filtration, ziprasidone intramuscular should be administered with caution to patients with impaired renal function.

Hepatic impairment.

In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhosis, the serum concentrations after oral administration were 30% higher and the terminal half-life was about two hours longer than in normal patients.

5.3 Preclinical Safety Data

Genotoxicity.

Ziprasidone hydrochloride was tested for genotoxic potential in assays for gene mutation and chromosomal damage. There was a reproducible response in the Ames assay in one strain of S. typhimurium in the absence of metabolic activation. Equivocal results were obtained in both the in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes. Ziprasidone hydrochloride was negative in the in vivo chromosomal aberration assay in mouse bone marrow.

Carcinogenicity.

Lifetime carcinogenicity studies were conducted with ziprasidone hydrochloride administered in the diet to rats and mice. In rats, there was no evidence of increased tumour incidences at doses up to 12 mg/kg/day, corresponding to systemic exposure (plasma AUC0-24 h) similar to that in humans at the maximum recommended dose. In male mice, there was no increase in tumour incidences at doses up to 200 mg/kg/day, corresponding to systemic exposure about 2.5 times that in humans. In female mice, dose related increases in the incidence of hyperplasia and neoplasia in the pituitary (shown immunohistochemically to be prolactin producing) and mammary gland were seen at 50 to 200 mg/kg/day, corresponding to systemic exposure about 1 to 4 times greater than that in humans; a no effect dose level for these effects was not established. Proliferative changes in the pituitary and mammary glands of rodents have been observed following chronic administration of other antipsychotic agents and are associated with increased prolactin concentrations. Although clinical and epidemiological studies have not shown an association between chronic administration of this class of drugs and tumourigenesis in humans, the use of ziprasidone in patients with familial history or previously detected breast cancer should be avoided. Caution should be exercised when considering ziprasidone treatment in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sulfobutyl betadex sodium (SBECD); water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products or solvents other than Sterile Water for Injections.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, store at 2-8°C (Refrigerate. Do not freeze) for not more than 24 hours.
Store below 30°C in dry form. Do not freeze. Protect from light.
Keep vials in the original pack until ready to use.

6.5 Nature and Contents of Container

Zeldox IM is presented in a single dose vial.
An ampoule containing 1.2 mL of Sterile Water for Injections Ph. Eur. is also supplied for reconstitution purposes.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Ziprasidone is an antipsychotic agent chemically unrelated to phenothiazine or butyrophenone antipsychotic agents.
The chemical name for ziprasidone mesilate is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, methanesulfonate, trihydrate.
Australian Approved Names: Ziprasidone (C21H21ClN4OS) and Ziprasidone mesilate (C21H21ClN4OS.CH3SO3H.3H2O).
The molecular formula of ziprasidone mesilate is C21H21ClN4OS.CH3SO3H.3H2O. Ziprasidone mesilate has a molecular weight of 563.09 and the free base has a molecular weight of 412.94.
Ziprasidone is a white to off-white powder. Ziprasidone mesilate is slightly soluble in methanol (5.0 mg/mL) and water (1.1 mg/mL) and practically insoluble in tetrahydrofuran (0.09 mg/mL). The solubility of ziprasidone mesilate in 30% (w/v) sulfobutyl betadex sodium (SBECD) was determined to be 45 mg/mL.

CAS number.

The CAS Registry Numbers are 146939-27-7 (ziprasidone) and 185021-64-1 (ziprasidone mesilate).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes